Degeneration of the cholangiocytes that comprise the liver's bile transporting (biliary) network is a major cause of liver failure, and account for approximately one third of all patients referred for liver transplantation. While the structure and function of the mature network has been well-characterized, the process of biliary development and morphogenesis is not well understood. This is particularly relevant, as most cholangiopathies involve a loss of differentiated cholangiocytes. Preliminary studies in the sakaguchi lab have identified cyclin-dependent protein kinase 5 (CDK5) as a regulator of cholangiocyte morphogenesis by promoting outgrowth of cellular projections that are required for a functional biliary network. CDK5 has previously been found to be a major player in the regulation of the formation of neuronal projections during development, and this project will focus on evaluating the role of known pathways that operate through CDK5 in the regulation of cholangiocyte morphogenesis. Understanding the mechanisms that regulate cholangiocyte differentiation and morphology will provide insight into the opposite process observed in cholangiopathies, in which projections retract and differentiation is lost. This information would represent a significant step toward treating a class of diseases that affect thousands of individuals and have poor long-term outcomes. PUBLIC HEALTH RELEVANCE: The biliary network is essential for basic liver function, and cholangiopathies (e.g., primary biliary cirrhosis and primary sclerosing cholangitis) are a major cause of chronic liver disease. This study aims to identify the mechanisms by which the biliary network develops and maintains its differentiated state, which is particularly relevant, as most known cholangiopathies result in a loss of cholangiocyte morphology and differentiation. The goal of this work is in develop a better understanding of cholangiocyte cell biology that will lead to potential therapeutic targets.